Abdominal aortic aneurysms (AAAs) exhibit pronounced sexual dimorphism. Similar to humans, we demonstrated previously that testosterone is a primary contributor to a 4-fold higher incidence of angiotensin II (AngII)-induced AAAs in male compared to female mice. In addition to sex hormones, sex chromosomes have been suggested to contribute to sexual dimorphism of cardiovascular diseases. Preliminary data demonstrate that changing the sex chromosome complement from XX to XY in female mice results in an AAA incidence that is similar to males. As testosterone promotes AngII-induced AAAs in XY males, we administered testosterone to neonatal (1 dose) and adult XY females. Testosterone caused aneurysm rupture in 73% of adult XY females. These results demonstrate that sex chromosome complement has a striking impact on AAA severity, and that these effects are augmented by testosterone. Gene arrays on smooth muscle cells from XX versus XY females incubated with AngII or testosterone identified neprilysin and heme oxygenase 1 (HO1) as gene targets that may contribute in a sex-specific manner to higher AAA incidences, severity and progression in males compared to females. The central hypothesis of this proposal is that an interplay between sex hormones and chromosomes promotes the incidence and severity of AAAs. Moreover, we hypothesize that a Precision Medicine approach to therapeutically target specific pathways influenced by sex hormones, chromosomes, or AngII will provide sex-specific efficacy against AAA formation and progression. Aim 1 will test the hypothesis that an XY sex chromosome complement increases susceptibility to AngII-induced AAAs due to the presence of genes on the Y chromosome. We will use a novel mouse model (XY*) that when bred to XX females enables delineation of whether XX, XO, XXY, or XY sex chromosome complement influences the development and/or progression of AngII-induced AAAs. Aim 2 will test the hypothesis that sex-specific therapeutic approaches, targeting neprilysin inhibition in males versus HO1 stimulation in females will provide efficacy against the formation and/or progression of AngII-induced AAAs. These studies will increase basic knowledge of sex chromosome influences on the vasculature, identify sex-specific therapies that may have therapeutic applicability against AAAs, and increase cardiovascular knowledge for the use of sex hormones in the growing trans-gender population.